Oral cancer typically presents as a very malignant tumor. More than 90 percent of oral cancers are squamous cell carcinoma which also is one of the most common malignant types occurring lung, skin, and ovary. At advanced stage, p53 is mutated in about 60 percent of tumors and the effectiveness of chemotherapy and radiotherapy has been very disappointing. Therefore, improving the efficacy of these therapies has become an urgent topic for both clinical oncologists and basic scientists. There is increasing evidence that apoptosis plays a critical role in the response to chemotherapy and radiotherapy. Resistance to apoptosis is likely to serve as a primary mechanism whereby tumor cells are able to escape chemo- and radio-therapy killing. Recently, this laboratory has observed that the transcription factor NF-kappaB is activated by several chemotherapeutic compounds and ionizing irradiation, and inhibition of NF-kappaB enhanced the apoptotic response of these stimuli in human fibrosarcoma model system in vitro and in vivo. The specific aims proposed in this application are the following: 1). Determine whether chemotherapy and radiotherapy activate NF- kappaB in oral squamous cell carcinoma and whether inhibition of NF-kappaB potentiates apoptosis of oral SCC induced by these therapies in vitro. 2). Explore the molecular mechanisms involved in NF-kappaB suppression of cancer therapy-mediated apoptosis. The role of NF-kappaB-induced genes c-IAP1 and 2 will be examined. 3). Determine whether inhibition of NF-kappaB as a neoadjuvant will enhance the efficacy of oral cancer therapy in a nude mouse model. We will utilize adenovirus-mediated delivery of super-repressor-IkappaBalpha and proteasome inhibitors to block the activation of NF-kappaB in vivo and determine whether these approaches will effectively inhibit the tumor growth in vivo. 4). Identify chemo- and radio-resistant genes by genetic screening. By using a unique cell line HT1080I cells that is sensitive to cancer therapy-induced apoptosis, efforts will be made to identify chemo- and radio-resistant genes from oral squamous cell carcinoma utilizing retroviral cDNA-based functional cloning. These studies will uncover the genetic mechanism of oral cancer resistance to cancer therapy and have an important implication in improving the efficacy of oral cancer therapy.